Alzheimer's disease (AD) research has shown that patients with an inherited form of the disease carry mutations in the presenilin proteins or the amyloid precursor protein (APP). These disease-linked mutations result in increased production of the longer form of amyloid-beta (the primary component of the amyloid deposits found in AD brains). However, it is not clear how the presenilins contribute to this increase. New findings now show that the presenilins affect APP processing through their effects on gamma-secretase, an enzyme that cleaves APP. Also, it is known that the presenilins are involved in the cleavage of the Notch receptor, hinting that they either directly regulate gamma-secretase activity or themselves are protease enzymes. These findings suggest that the presenilins may prove to be valuable molecular targets for the development of drugs to combat AD.

The presenilins in Alzheimer's disease--proteolysis holds the key.

Neurodegenerative disorders, which are chronic and progressive, are characterized by selective and symmetric loss of neurons in motor, sensory, or cognitive systems. Delineation of the patterns of cell loss and the identification of disease-specific cellular markers have aided in nosologic classification: senile plaques, neurofibrillary tangles, neuronal loss, and acetylcholine deficiency define Alzheimer's disease1,2; Lewy bodies and depletion of dopamine characterize Parkinson's disease3; cellular inclusions and swollen motor axons are found in amyotrophic lateral sclerosis4; and γ-aminobutyric acid–containing neurons of the neostriatum are lost in Huntington's disease.5 Mendelian inheritance can be demonstrated in many of these disorders . . .

Molecular basis of the neurodegenerative disorders.

Diseases of aging.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/S0014-5793%2800%2901323-5

The amyloid β peptide Aβ (25–35) induces apoptosis independent of p53

We and colleagues have shown that the amyloid protein precursor of Alzheimer's disease (APP) is distributed along the surface of neurites of fixed but nonpermeabilized neurons in primary culture in a segmental pattern, which shows colocalization with some markers of adhesion patches. This is in contrast to the diffuse pattern of immunoreactivity seen after permeabilization. We have also recently demonstrated that the APP in these surface patches is likely to be integral to the membrane rather than secreted and re-adsorbed, based on alkali stripping experiments and on soluble APP adsorption experiments. Total cellular APP has previously been shown to have a short half-life of approximately 30-60 min. We confirm this in neurons in primary culture in pulse-chase experiments using short labelling times. Additionally, we provide evidence that a separate, stable pool of neuronal APP can be demonstrated in pulse-chase experiments using long labelling times. Experiments involving inhibition of protein synthesis suggest that this corresponds with the surface, segmental pool. Metabolic labelling followed by surface biotinylation and two-stage precipitation demonstrates that the surface APP is trans-membrane and full-length (not carboxyl-terminal truncated), and confirms that the surface APP belongs to the stable pool. This two-stage procedure is necessary as the surface APP appears to be present in low copy number, and is difficult to detect by direct labelling. This information is consistent with a role for APP in stable cell-matrix or cell-cell interactions.

Amyloid precursor protein of Alzheimer's disease: evidence for a stable, full-length, trans-membrane pool in primary neuronal cultures.

Amyloid β-peptide (Aβ), the major component of senile plaques, is generated by proteolytic processing from the β-amyloid precursor protein (βAPP). Mutations within the βAPP gene cause early onset familial AD (FAD) by affecting Aβ generation. Interestingly, the much more abundant mutations within the presenilin (PS) genes also result in the abnormal generation of a 42 residue Aβ (Aβ42), thus clearly supporting a pivotal role of Aβ for the pathology of AD. PS proteins are proteolytically processed into stable 30kDa N-terminal fragments (NTF) and 20kDa C-terminal fragments (CTF). Beside the conventional proteolytic pathway, PS proteins can also be cleaved further C-terminal by proteases of the caspase superfamily. PS proteins were localized within the endoplasmic reticulum (ER) and early Golgi, compartments which we have demonstrated to be involved in Aβ42 generation and intracellular accumulation. Using Caenorhabditis elegans as a simple animal model, we demonstrate that PS proteins are involved in NOTCH signaling. FAD causing mutations interfere with the biological function of PS proteins in NOTCH signaling.

Proteolytic processing of Alzheimer’s disease associated proteins

Presenilin (PS) proteins are involved in numerous cases of familial Alzheimer’s disease (reviewed by Tanzi et al. 1996) and are therefore key players in the pathogenesis of the disease. To understand the biology of the PS proteins we searched for a potential biological function and analyzed the biochemistry of the two homologous PS proteins. We also determined the subcellular localization of presenilis and took advantage of this knowledge to search for a cellular mechanism that is involved in Aβ42 generation. These three main topics will be reviewed in detail.

The Cellular Biology of Presenilin Proteins and a Novel Mechanism of Amyloid β-Peptide Generation

Handle everyday research tasks with reliable, citation-backed results

Your personal Research Agent to handle research tasks with citation-backed results

Popular Tasks used by Researchers

How can I help with your research?

Meet SciSpace

Get more enhanced response by uploading the PDFs you want me to reference.

No relevant PDFs in your library

SciSpace is the AI research assistant for academics. Run systematic literature reviews on 280M+ papers, and write papers with cited sources. Trusted by 1M+ students, PhDs & researchers.

SciSpace | AI for Research

Analyze PDFs

Code & Manuscripts

Funding & Grants

Literature & Patents

Medical & Clinical Data

Systematic Review

Visualize & Present

Web & Data

Build a Google Scholar-like website for your research.

Build a website

Create charts and images for your research

Create a Chart

Write a paper for submission to a journal

Draft a manuscript

Patent Search

Design eye-catching scientific posters in minutes.

Scientific Poster Generation

Systematic Literature Review

One task is running at the moment. Your messages will be shown right after.

Drag and drop or click here to browse

Loved by <highlight>1 million+</highlight> researchers

Extract a list of specific topics and their sources from unstructured text

Topics

Compare and analyze relevant papers that matches with your search

Papers

Get insights from PDFs and bookmarked papers from your library

My library

Recent searches

Try searching for:

Catch AI-generated content in scholarly and non-scholarly content

{ai} Detector

Ai Writer

Get PDF Summaries, highlighted text explanations 

Chat with PDF

Effortlessly create in-text citations and bibliographies in APA and 2,500 other formats

Citation generator

Get explanations, summaries, and answers on academic papers

Ease up your research workflow with {scispace}'s cohort of exciting AI tools

Elevate your academic writing skills and convey your ideas the way you want

Paraphraser

Explore our range of reading and writing tools

Your file is being prepared and should be ready in a few minutes. If it's a large file, it might take a bit longer. You can close this window, and we'll email you the file when it's done.

You have reached a maximum limit of <strong>{limit}</strong> columns in the table. Remove at least <strong>1</strong> column to add or create another one.

I. Ihara

Author Tools

Chat about Author

Papers

Proteolytic processing of Alzheimer’s disease associated proteins

The Cellular Biology of Presenilin Proteins and a Novel Mechanism of Amyloid β-Peptide Generation